Dra bartolome's neoplasia review
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NEOPLASIA REVIEWFe A. Bartolome, MD, FPASMAPDepartment of PathologyOur Lady of Fatima University
Nomenclature
Benign tumors
1. Suffix “oma” generally indicates a benign tumor
2. Benign tumors of epithelial origina. Arise from ectoderm or endodermb. Example – tubular adenoma arising
from glands in the colon
3. Benign tumors of connective tissue origin arise from mesoderm• Example – lipoma from adipose
Nomenclature
Benign tumors
4. Tumors that are usually benign
a. Mixed tumors• Neoplastic cells have two different
morphologic patterns but derive from the same germ cell layer
• Example – pleiomorphic adenoma of parotid gland
Nomenclature
Benign tumors
4. Tumors that are usually benign
b. Teratomas • Tumors that derive from more than
one germ cell layer – contain tissue derived from ectoderm, endoderm, and mesoderm
• Sites: ovaries, testes, anterior mediastinum, and pineal gland
Nomenclature
Malignant tumors (cancers)
1. Carcinomasa. Derive from epithelial tissue –
squamous, glandular, transitionalb. Sites of squamous cell carcinoma• Oropharynx, larynx, upper/middle
esophagus, lung, cervix, skinc. Sites of adenocarcinoma• Lung, distal esophagus to rectum,
pancreas, liver, breast, endometrium, ovaries, kidneys, prostate
Nomenclature
Malignant tumors (cancers)
2. Sarcomas
a. Derive from connective tissue
b. Example – osteogenic sarcoma in bone
Nomenclature
Tumor-like Conditions
1.Hamartoma a. Non-neoplastic overgrowth of
disorganized tissue indigenous to a particular site
b. Examples – bronchial hamartoma, Peutz-Jeghers polyp
2.Choristoma (heterotopic rest)a. Non-neoplastic normal tissue in a foreign
locationb. Examples – pancreatic tissue in stomach
wall; gastric mucosa in Meckel diverticulum
Properties
Components of benign & malignant tumors
1.Parenchyma• Neoplastic component that determines the
tumor’s biologic behavior
2.Stroma • Non-neoplastic supportive tissue• Most infiltrating carcinomas induce
production of a dense, fibrous stroma
Properties
Differentiation
1.Benign tumors• Usually well-differentiated – resemble
parent tissue
2.Malignant tumorsa. Well-differentiated or low gradeb. Poorly-differentiated, high grade, or
anaplasticc. Intermediate grade – features between
low- and high-grade cancers
Properties
Nuclear Features
1.Benign tumors• Nuclear:cytoplasmic ratio close to normal• Mitoses with normal mitotic spindles
2.Malignant tumorsa. Nuclear:cytoplasmic ratio increased with
prominent nucleolib. Mitoses have normal and atypical mitotic
spindles
Properties
Growth Rate
1.Benign tumors• Usually with slow growth rate
2.Malignant tumors• Variable growth rate – correlates with
degree of differentiation• Anaplastic cancers with increased growth
rate• 30 doubling times required for a tumor to
be clinically evident equivalent to 109 cells, 1 gram of tissue, volume of 1 ml
Properties
Monoclonality
•Benign and malignant tumors derive from a single precursor cell
•Non-neoplastic proliferations derive from multiple cells (polyclonal)
Properties
Telomerase Activity
1.Telomerase functiona. Preserves length of telomeres (sequences
of non-translated DNA at the ends of chromosomes)
b. Prevents gene loss after multiple cell division
2.Benign tumors with normal telomerase activity
3.Malignant tumors with increased telomerase activity do not lose genetic material after multiple cell division
Properties
Local Invasion• Second most important criterion for
malignancy1.Benign tumors do not invade usually enclosed in a fibrous capsule (except uterine leiomyoma)
2.Malignant tumors invade tissue• Basal cell CA of the skin invade tissue but
do not metastasize
3.Some tissues resist invasion – mature cartilate, elastic tissue in arteries
Properties
Local Invasion
Sequence of invasion by malignant tumors:1.Loss of intercellular adherence• E-cadherin not produced
2.Cell invasion occursa. Cell receptors attach to laminin
(glycoprotein in the basement membrane)b. Cells release type IV collagenase
dissolve BMc. Cell receptors attach to fibronectin in the
ECMd. Cells produce cytokines (stimulate
locomotion) and proteases (dissolve connective tissue)
e. Cells produce factors that stimulate angiogenesis (EGF, bFGF)
Properties
Metastasis
•Benign tumors do not metastasize•Malignant tumors metastasize
Pathways:1. Lymphatic spread to lymph nodes –
usual for carcinomas2. Hematogenous
Usual for sarcomas Cells entering portal vein liver Cells entering vena cava lungs
3. Seeding – malignant cells exfoliate from surface and implant and invade tissue in a body cavity
Properties
Metastasis
•Bone metastases
1. Vertebral column Most common metastatic site in bone Due to Batson paravertebral venous
plexus2. Osteoblastic metastases
Radiodensities seen on radiograph (eg prostate cancer)
Increased serum alk phos reactive bone formation
Properties
Metastasis
•Bone metastases
3. Osteolytic metastases Radiolucencies on radiographs (eg lung
CA) Pathogenesis:
a. Production of substances that activate osteoclasts (e.g. PGE2, IL-1)
b. Production of parathyroid hormone-related protein (e.g. Squamous cell CA in lungs, renal cell CA)
Consequences: pathologic fractures, hyper-calcemia
Properties
Metastasis
•Metastasis often more common than a primary cancer
a. Lymph nodes – metastatic breast and lung CA
b. Lungs – metastatic breast CAc. Liver – metastatic lung CAd. Bone – metastatic breast CAe. Brain – metastatic lung CA
Acquired neoplastic disorders
1. Autosomal dominant cancer syndrome
a. Retinoblastoma – inactivation of RB suppressor gene
b. Familial adenomatous polyposis - inactivation of APC suppressor gene; colorectal cancer by age 50
c. Li-Fraumeni syndrome – inactivation of TP53 suppressor gene
d. Hereditary nonpolyposis colon cancer (Lynch syndrome) – DNA mismatch repair genes
e. Breast & ovarian cancer – BRCA1 and BRCA2 genes
Acquired neoplastic disorders
2. Autosomal recessive syndromes with defects in DNA repair
a. Xeroderma pigmentosum – skin cancer due to UVL (basal cell CA, squamous cell CA)
b. Chromosome instability syndromes – damage by ionizing radiation and drugs• Include Fanconi anemia, ataxia
telangiectasia, Bloom syndrome
Acquired neoplastic disorders
3. Familial cancer syndromes
• No defined pattern of inheritance
• Cancers (breast, ovary, colon) develop with increased frequency in families
• Sometimes involves BRCA1 and BRCA2 genes
Carcinogenesis
Types of gene mutation
1. Point mutations – most common type
2. Balanced translocations
3. Other mutations• Deletion, gene amplification (multiple
copies of a gene), over-expression (increase in baseline gene activity
Carcinogenesis
Genes involved in cancer
1. Proto-oncogenes
• Involved in normal growth and repair• Protein products include: growth
factors, growth factor receptors, signal transducers, nuclear transcribers
• Mutations cause sustained activity of the genes
Carcinogenesis
Genes involved in cancer
2. Suppressor genes (anti-oncogenes)
• Protect against unregulated cell growth• Control G1 to S phase of the cell cycle
and nuclear transcription• Mutations cause unregulated cell
proliferation
Carcinogenesis
Genes involved in cancer
3. Anti-apoptosis genes (BCL2 family of genes)
• Protein products prevent cytochrome c from leaving the mitochondria
• Mutation causes increased gene activity (e.g.overexpression) prevents apoptosis (e.g. B-cell follicular lymphoma) Translocation t(14:18) cause over-
expression of BCL2 protein prevent apoptosis of B cells
Carcinogenesis
Genes involved in cancer
4. Apoptosis genes
• Regulate programmed cell death• Example – BAX apoptosis gene
a. Activated by TP53 if DNA damage is excessive
b. Protein product inactivates BCL2c. Inactivation of TP53 BAX
inoperative no apoptosis
Carcinogenesis
Genes involved in cancer
5. DNA repair genes
• Examples of DNA repaira. Mismatch repair genes – correct
errors in nucleotide pairingb. Nucleotide excision repair – excise
pyrimidine dimers in UVL-damaged skin
• Mutation allows cells with non-lethal damage to proliferate increased risk for cancer
Chemical Carcinogens
1. Polycyclic hydrocarbons in tobacco smoke• Most common group of carcinogens in the
USA
2. Mechanisms:a. Direct-acting carcinogens• With electron-deficient atoms that react
with electron-rich atoms in DNA (e.g. Alkylating agents)
b. Indirect-acting carcinogens• Activated by the liver cytochrome P-450
system (e.g. Polycyclic hydrocarbons)
Chemical Carcinogens
3. Sequence of chemical carcinogenesis
a. Initiation• Irreversible mutation
b. Promotion• Promoters (e.g. Estrogen) stimulate
mutated cells to enter the cell cycle
c. Progressioni. Development of tumor heterogeneityii. Examples – production of cells that
invade or metastasize
Microbial Carcinogenesis
Radiation
1. Ionizing radiation• Hydroxyl free radical injury to DNA• Examples: AML or CML; papillary thyroid
CA; lung, breast or bone cancers• Leukemia – most common cancer due to
ionizing radiation
2. UV light• Formation of pyrimidine dimers distort
DNA• Examples: basal cell CA (most common),
squamous cell CA, malignant melanoma
Host Defense vs. Cancer
1. Humoral immunity – antibodies and complement
2. Type IV cellular immunity• Most efficient mechanism• Cytotoxic CD8 T cells – recognize altered
class I antigens on neoplastic cells and destroy them
3. Natural killer cells – direct and indirect killing via type II hypersensitivity
4. Macrophages – activated by gamma-interferon
Cancer Grading
• Degree of differentiation Low, intermediate, or high
grade
• Nuclear features
• invasiveness
Cancer Staging
• Most important prognostic factor• TNM system
1. Progresses from the least to the most important prognostic factor
2. T – tumor size > 2 cm correlates with metastatic ability
3. N – nodal involvement4. M – extranodal metastases
Cancer Effects on Host
1. Cachexia (wasting disease)
• Irreversible catabolic reaction• Mechanism: tumor necrosis factor-
alphaa. Secreted from host macrophages
and cancer cellsb. Suppresses the appetite centerc. Increases beta-oxidation of fatty
acids
Cancer Effects on Host
2. Anemia
a. Anemia of chronic diseaseb. Iron deficiency due to GI blood lossc. Macrocytic anemia – due to folate
deficiency from rapid tumor growthd. Myelophthisic anemia• Anemia related to bone metastasis• Immature hematopoietic elements
in peripheral blood Teardrop RBCs indicate myelo-
fibrosis secondary to bone metastasis
Cancer Effects on Host
3. Hemostasis abnormalities
a. Increased risk for vessel thrombosis• Due to thrombocytosis, increased
synthesis of coagulation factors (fibrinogen, factors V and VIII)
• Release of pro-coagulants from cancer cells (e.g. Pancreatic CA)
b. DIC due to release of tissue thromboplastin from cancer cells
Cancer Effects on Host
4. Paraneoplastic syndromes
a. Distant effects of a tumor that are unrelated to metastasis – may predate the onset of metastasis
b. Occur in 10-15% of cancer patientsc. Involve multiple organ systems and
mimic metastatic diseased. May involve ectopic secretion of
hormone
Cancer Effects on Host
Syndrome Associated cancer Comment
Acanthosis nigricans Stomach carcinoma Black verrucoid-appearing lesion
Eaton –Lambert synd. Small cell CA of lung Myasthenia gravis-like symptoms
Hypertrophic osteoarthropathy
Bronchogenic CA Periosteal reaction of distal phalanx
Nonbacterial thrombotic endocarditis
Mucus-secreting pancreatic and colorectal carcinomas
Sterile vegetations on mitral valve
Seborrheic keratosis Stomach carcinoma Sudden appearance of numerous pigmented seborrheic keratoses (Leser-Trelat sign)
Superficial migratory thrombophlebitis
Pancreatic carcinoma Release of pro-coagulants (Trosseau sign)
Cancer Effects on Host
Disorder Associated cancer Ectopic hormone
Cushing syndrome Small cell CA of lung, medullary thyroid CA
ACTH
Gynecomastia Choriocarcinoma (testis)
hCG
Hypercalcemia Renal cell CA, primary SCCA lung, breast CA
PTH-related protein
Hypocalcemia Medullary thyroid CA Calcitonin
Hypoglycemia Hepatocellular CA Insulin-like factor
Hyponatremia Small cell CA of lung ADH
Secondary polycythemia
Renal cell and hepato-cellular CA
erythropoietin
Tumor Markers
• Biologic markers
• Include hormones, enzymes, oncofetal antigens, glycoproteins
• Identify tumors
• Estimate tumor burden
• Detect recurrence
Tumor Markers
Tumor marker Associated cancer
AFP Hepatocellular CA, yolk sac tumor (endodermal sinus tumor) of ovary or testis
Bence Jones protein
Multiple myeloma, Waldenstrom’s macroglobulinemia (represent light chains in urine)
CA 15-3 Breast carcinoma
CA 19-9 Pancreatic carcinoma
CA 125 Surface-derived ovarian cancer (e.g. Serous cystadenocarcinoma)
CEA Colorectal and pancreatic carcinomas
PSA Prostate carcinoma (also increased in prostate hyperplasia)
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